The long-term goal of this proposal is to understand the contribution of T lymphocytes to joint inflammation and destruction in rheumatoid arthritis (RA). T lymphocytes represent a major cell population in the inflamed synovium. By analyzing the molecular diversity of synovial T cells in early disease, we have recently observed that the repertoire of IL-2 receptor expressing CD4+ T cells is markedly biased with the preferential involvement of T cells utilizing a core group of T cell receptor (TCR) Vbeta elements. Within such T cell populations, we have identified single specificities which were clonally expanded indicating that they have recently contacted antigen or superantigen and thus represent potentially disease relevant T cells. Identical T cell specificities were found in high frequencies in the peripheral blood raising the hypothesis that stimulation and proliferation of selected T cell specificities in early RA patients is not limited to the joint. This application proposes a comprehensive analysis of the TCR repertoire in early synovial lesions with the aim to dissect disease relevant T cells from T cells nonspecifically accumulated at a site of inflammation. The rationale for focusing on early disease comes from recent studies demonstrating that autoimmune T cell responses induced by immunization with self-peptides have a tendency to diversity and to involve a heterogeneous T cell population over time. Specifically, we will expand our studies on the subset of IL-2 responsive CD4+ T cells in early synovitis to define whether the pattern of T cell specificities we have defined is shared by all patients with RA and is unique for rheumatoid synovitis as opposed to other inflammatory arthritides. We will continue to identity and to characterize clonally expanded T cell specificities, study their distribution in peripheral blood and the synovia, and investigate whether the mechanism driving proliferation of selected T cells is antigen-specific or suggestive of a superantigen. Longitudinal monitoring of the synovial TCR repertoire will concentrate on tracing clonally expanded TCR specificities over two years and will also address the question whether the progression of the disease relates to the recruitment and activation of new specificities. Identification of T cell clones eliciting an immune response in early synovitis would provide a unique reagent in the search for the disease inducing agents and in the development of targeted therapeutic interventions.